The goal of this project is to examine the relation between partial remyelination in the injured nervous system and the clinically significant problem of action potential conduction block. These studies will be performed in a guinea pig model of chronic spinal cord injury and will involve intracellular recording from myelinated nerve fibers within strips of spinal cord white matter isolated in artificial media. The physiological responses and conduction properties of these fibers will be recorded and related to the characteristics of their myelin sheaths, as determined by intracellular injection of the marker biocytin and subsequent morphologic reconstruction from serial sections. This information will be used to explore the relation between morphological and physiological changes using computer based mathematical models of action potential conduction. A broader survey of the range of myelination deficits in these white matter tracts will also be performed by conventional means of osmium tetroxide fixation and teasing apart of single fibers. A particular goal of this study will be to identify differences between axons that respond and those that do not respond to the application of 4- aminopyridine (4-AP) with a change in the temperature of conduction block or of frequency-response characteristics. Previous experiments have shown that 4-AP, a potassium channel blocking drug, can restore conduction of impulses in some axons of chronically injured spinal cord that otherwise fail to conduct at physiological temperature. The same drug has also been shown to improve neurologic function in animals and human subjects with chronic spinal cord injury, and may prove to be a useful symptomatic treatment, particularly in some cases of incomplete spinal cord injury. It is important to understand the cell physiological basis of these responses, in order to optimize this approach to reducing functional deficits following injury to the nervous system. The experiments will address the potential role of a number of factors in the relation between changes in the myelination of central axons and their conduction characteristics. These include the dimensions of node and internode, with attendant effects on impedance matching; changes in the resting potential of the nerve fiber and their influence on excitability; alterations in the accumulation of extracellular potassium as a result of action potential transmission; and direct involvement of internodal ion channels exposed to large electrical potential transients as a result of dramatic reductions of myelin sheath thickness. A mathematical model of the myelinated axon will be used to explore the possible interaction between these factors and the blockade of voltage-dependent potassium channels, equivalent to the effects of CAP and other drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033687-03
Application #
2460597
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Cheung, Mary Ellen
Project Start
1995-08-15
Project End
1998-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Surgery
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Yates, J R; Gay, E A; Heyes, M P et al. (2014) Effects of methylprednisolone and 4-chloro-3-hydroxyanthranilic acid in experimental spinal cord injury in the guinea pig appear to be mediated by different and potentially complementary mechanisms. Spinal Cord 52:662-6
Luo, Jian; Uchida, Koji; Shi, Riyi (2005) Accumulation of acrolein-protein adducts after traumatic spinal cord injury. Neurochem Res 30:291-5
Luo, Jian; Borgens, Richard; Shi, Riyi (2004) Polyethylene glycol improves function and reduces oxidative stress in synaptosomal preparations following spinal cord injury. J Neurotrauma 21:994-1007
Luo, Jian; Shi, Riyi (2004) Diffusive oxidative stress following acute spinal cord injury in guinea pigs and its inhibition by polyethylene glycol. Neurosci Lett 359:167-70
Luo, Jian; Shi, Riyi (2004) Acrolein induces axolemmal disruption, oxidative stress, and mitochondrial impairment in spinal cord tissue. Neurochem Int 44:475-86
Shi, R; Luo, J; Peasley, M (2002) Acrolein inflicts axonal membrane disruption and conduction loss in isolated guinea-pig spinal cord. Neuroscience 115:337-40
Luo, Jian; Borgens, Richard; Shi, Riyi (2002) Polyethylene glycol immediately repairs neuronal membranes and inhibits free radical production after acute spinal cord injury. J Neurochem 83:471-80
Shi, R; Asano, T; Vining, N C et al. (2000) Control of membrane sealing in injured mammalian spinal cord axons. J Neurophysiol 84:1763-9
LoPachin, R M; Gaughan, C L; Lehning, E J et al. (1999) Experimental spinal cord injury: spatiotemporal characterization of elemental concentrations and water contents in axons and neuroglia. J Neurophysiol 82:2143-53
Nygren, A; Halter, J A (1999) A general approach to modeling conduction and concentration dynamics in excitable cells of concentric cylindrical geometry. J Theor Biol 199:329-58

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